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ARTICLE IN BRIEF

In a 25-year retrospective review of treatment outcomes for patients with autoimmune cerebellar ataxia, researchers reported that immunotherapy proved helpful for some patients if they were treated early and aggressively. The study offers insights into the best candidates for therapy.

In a large retrospective study, some patients with autoimmune cerebellar ataxia experienced improvements on immunotherapy and remained ambulatory, according to a 25-year review of treatment outcomes published online September 28 in JAMA Neurology.

Generally, autoimmune cerebellar ataxia, which can be paraneoplastic or nonparaneoplastic, induces disabling neurologic deficits such as dysarthria, gait and balance disorders, and limb ataxia, the study authors noted. But there has been a dearth of published studies on treatment responses and neurologic outcomes, they wrote.

At least 17 autoantibodies have been associated with autoimmune cerebellar ataxia, but for the most part, the track record with immunotherapy has been poor, lead study author Andrew McKeon, MD, an associate professor of neurology at the Mayo Clinic in Rochester, MN, told Neurology Today. “We've learned from this review, however, that there are some patients who, if treated early and aggressively enough, could see considerable improvement,” he said.

STUDY PROTOCOLS, FINDINGS

The Mayo Clinic researchers reviewed the medical records of 118 patients with autoimmune cerebellar ataxia from 1989 to 2013. They included patients who were seropositive for at least one neural autoantibody and had been treated at least once with immunotherapy or cancer therapy (chemotherapy or radiation). Sixty-three had paraneoplastic disorders and 55 had nonparaneoplastic disorders.

Overall, 54 of the 118 patients (45.8 percent) improved — 51 with immunotherapy and three with cancer treatments, according to the reports. Twenty-two of these patients (19 percent) had a “robust” response, meaning they became more ambulatory.

Thirty-five percent (18 patients) in the nonparaneoplastic group had a robust response compared with four patients (8 percent) in the paraneoplastic group (p=0.002). The four patients who improved were found to have Purkinje cell cytoplasmic antibody type 1 (PCA-1), or the anti-Yo antibody. These patients generally do not respond to treatment, but in these cases, one patient who had been bedbound was able to use a walker after treatment, while another could walk independently, albeit with an abnormal gait.

Dr. McKeon noted that these four cases do not reflect the norm; of the 37 patients with PCA-1 antibodies, most had much less of a response or no response at all.

Among other findings, patients with GAD65 antibodies — neuronal nuclear and cytoplasmic antibodies (NNCs) that are thought to induce disease that is difficult to treat with immunotherapy — progressed more slowly in terms of becoming wheelchair-bound than those who did not have the antibodies (p<0.001). The progression for those positive for GAD65 antibodies was similar to those with only PMP antibodies (p=0.92).

What might explain this? Dr. McKeon said that patients with Stiff Person syndrome — for which GAD65 is a biomarker — have been found to have co-existing IgG that is reactive with cell surface antigens, including glycine receptor antibodies. The same thing might be happening in autoimmune cerebellar ataxia, he said.

“It's possible that there is some other antibody in these patients that we don't know about,” Dr. McKeon said. “In the field in general, there's one pertinent IgG antibody being added to testing repertoires about once every six to 12 months. So I think this is something that's evolving, and we're learning more and more about these patients.”

“Although detection of a paraneoplastic disorder or NNC antibody may portend a worse prognosis, this finding should not deter physicians from trials of immunotherapy in these patients because some may improve,” the researchers wrote. “Sequential trials of corticosteroids, plasma exchange, and intravenous immunoglobulin could be undertaken in any patient with autoimmune ataxia, including those with paraneoplastic disorders, although these patients are less likely to respond overall.”

Dr. McKeon suggested keeping an autoimmune disorder in mind when symptoms of cerebellar ataxia are quickly worsening and it's clear from the first evaluation and scan that a stroke or a tumor isn't to blame.

In those cases, he said, clinicians might suspect an autoimmune or paraneoplastic disorder. “A comprehensive antibody evaluation of serum and spinal fluid are important, as they will often give the diagnosis,” he said. “Sometimes people have favored doing a ‘one-antibody-one-disease’ kind of approach. Unfortunately, that isn't very helpful because these diseases progress rapidly and each antibody is rare. If we just take one antibody at a time, we could be testing for a very long time before reaching a diagnosis.”

EXPERT COMMENTARY

Brent Fogel, MD, PhD, an assistant professor of neurology at the University of California, Los Angeles (UCLA) and director of the UCLA Neurogenetics Clinic, who studies ataxia, said the report begins to shed light on the possibility that treatments can work in a group of patients previously thought to be short on hope.

There are no definitive figures on how many cases of sporadic ataxia are autoimmune, Dr. Fogel said, noting that “it's often not looked for very aggressively because much of the literature suggests that it usually doesn't respond well to therapy.”

The prevailing view, he said, is that “if you find a paraneoplastic disorder, the best therapy is to remove the associated cancer, but beyond that your chances for successful treatment become more limited. This study suggests that that may not be the case. Certainly this will encourage stronger consideration of these treatments in patients with autoimmune ataxia.”

He noted, however, that the study looked only at patients who tested positive for known antibodies, not taking into account those with only suspected autoimmune disease — a challenging clinical population to manage. But it suggests that those without detectable antibodies “might be amenable to treatment as well.”

It's unlikely that the antibodies are actually directly mediating disease, he said, because they wouldn't be able to reach the epitopes of those nuclear antigens inside the cell. So it's more likely that something else is mediating the disease. Therefore, if patients with those antibodies responded to therapy, it stands to reason that those with no detected antibodies might respond as well, Dr. Fogel said. There might be some other process at work that might respond to therapy.

Dr. Fogel added that while the researchers put their data to good use, the study was limited in that it was retrospective in design. The researchers reported on only those patients with clear improvement, not those whose progression was merely halted — information that would be useful to know, as not all patients show improvement and stabilization is often the first indication of a successful treatment approach.

In addition, he noted that no responses using validated measurements of ataxia severity were available, such as the SARA (Scale for the Assessment and Rating of Ataxia) score, so the overall improvement of the ataxia symptoms could not be clearly determined. The findings lay the foundation for a future study where such important points could be explored, he said.

“These findings are very promising and point to a need for a prospective or randomized study to develop a systematic approach to treatment,” Dr. Fogel said. “This report shows that treatments can work potentially very well in some of these patients. The next question is which are the best treatments, and for whom.”